Mennerick- ligand Binding Handout

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Mennerick-- Ligand Binding Handout - -



This institution (WUMS), like many medical schools, no longer has a Department of Pharmacology. Nevertheless all physicians prescribe drugs, and research scientists will all inevitably use pharmacology as a tool at some point in their research. Thus, despite the poor reputation that pharmacology has in today’s post-genomic era (“all drugs are dirty”), pharmacology continues to be ubiquitous, and I think it’s important that students are exposed to basic pharmacology principles.

Whether we’re talking about ligand-gated ion channels or about GPCRs, some basic principles apply.
First, the ligand’s interaction with the receptor can be modeled as a reversible, bi-molecular reaction. This means that we can write chemical equations to represent the drug-receptor interaction (subsequent pages).
Second, many terms are applicable no matter what the receptor type. Here is a partial glossary.
Ligand: any molecule that binds to a receptor. Examples: Nicotine, curare, and mecamylamine are ligands for the muscle nicotinic receptor.
Agonist: a ligand that activates the receptor (opens a ligand-gated channel or stimulates a G protein). Example: Nicotine is an agonist at the nicotinic receptor.
Antagonist: a ligand that has no biological effect on the receptor when it binds but reverses an agonist’s effect. Example: Curare and mecamylamine are antagonists at the endplate nicotinic receptor.
Competitive antagonist: An antagonist that competes with an agonist for the same (or overlapping) binding site. The effect of a competitive antagonist at steady state can therefore be overcome with higher free [agonist]. Example: Curare is a competitive antagonist at the endplate nicotinic receptor.
Non-competitive antagonist: An antagonist that binds to a site other than the agonist binding site.

Mecamylamine is a non-competitive antagonist at the nicotinic endplate receptor. Picrotoxin is a non-competitive antagonist at the GABAA receptor.

Uncompetitive antagonist: Like a non-competitive antagonist, binds to a separate site from the agonist, but requires channel opening for binding. Example: Jim Huettner showed in 1988 that MK-801 is an interesting example of an uncompetitive antagonist of the NMDA receptor (PNAS 85:1307). Ketamine (an anesthetic) and memantine (used in treatment of Alzheimer’s disease) are additional examples of uncompetitive NMDA receptor antagonists. [For simplicity, I sometimes dispense with the term “uncompetitive” and use “non-competitive”. This has gotten me into trouble with some peer reviewers]
Partial agonist. An agonist that binds to the receptor but does not activate the “full” response. For ligand-gated ion channels, this would be an agonist that binds but produces a lower channel opening/closing rate ratio than a full agonist.
Inverse agonist. A ligand that binds the receptor at the agonist site, but unlike a competitive antagonist, promotes a conformational change in the receptor that promotes channel closure. For example: Joe Henry Steinbach’s lab showed in 1997 that bicuculline, long thought to be a competitive antagonist at the GABAA receptor, is actually an inverse agonist (J Neurosci 17:625).
Allosteric. A ligand that works from a site other than a reference site of action, usually the site of agonist binding. Example: benzodiazepines positively allosterically regulate GABAA receptor function.
Potency: A dangerous term because it means different things to different people. I use potency as an empirical term equivalent to EC50 (agonist) or IC50 (antagonist) (see lecture). Others use it with a connotation closer to Kd.
Efficacy: How “full” is the agonist action? A partial agonist is a low-efficacy agonist (but it can still have high potency if concentration needed to generate the response is low). An antagonist has zero efficacy.

Start with the simple scheme of drug binding to a single site:

k1 = rate constant for association (units: M-1 s-1)

k2 = rate constant for dissociation (units: s-1)

A = drug

Y = proportion of receptors occupied by drug (=[AR]/([AR]+[R])

R = receptor

AR = receptors bound by agonist

Rtotal = total receptors (=[AR] + [R])

Note that AR  A + R is a first order reaction, like radioactive decay. The rate of dissociation will be dependent on the concentration of remaining [AR]. It is an exponential decay process with a time constant the reciprocal of k2.
The reaction A + R  AR in the other direction is called a pseudo first-order reaction. This is when agonist [A] is present in great excess compared to [R]. [A] will not change over the course of the experiment, and

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